The present invention relates to compounds which are antagonists of gonadotropin releasing hormone (GnRH) activity. The invention also relates to pharmaceutical formulations, the use of a compound of the present invention in the manufacture of a medicament, a method of therapeutic treatment using such a compound and processes for producing the compounds.
Gonadotropin releasing hormone (GnRH) is a decapeptide that is secreted by the hypothalamus into the hypophyseal portal circulation in response to neural and/or chemical stimuli, causing the biosynthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary. GnRH is also known by other names, including gonadoliberin, LH releasing hormone (LHRH), FSH releasing hormone (FSH RH) and LH/FSH releasing factor (LH/FSH RF).
GnRH plays an important role in regulating the action of LH and FSH (by regulation of their levels), and thus has a role in regulating the levels of gonadal steroids in both sexes, including the sex hormones progesterone, oestrogens and androgens. More discussion of GnRH can be found in WO 98/5519 and WO 97/14697, the disclosures of which are incorporated herein by reference.
It is believed that several diseases would benefit from the regulation of GnRH activity, in particular by antagonising such activity. These include sex hormone related conditions such as sex hormone dependent cancer, benign prostatic hypertrophy and myoma of the uterus. Examples of sex hormone dependent cancers are prostatic cancer, uterine cancer, breast cancer and pituitary gonadotrophe adenoma.
The following disclose compounds purported to act as GnRH antagonists: WO 00/04013, WO 99/41252, WO 99/41251, WO 98/55123, WO 97/21704, WO 97/21703, WO 97/21707, WO 97/21435, WO 97/44041, WO 98/55119, WO 99/51596 and WO 97/14697.
It would be desirable to provide further compounds, such compounds being GnRH antagonists.
The present invention accordingly provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof 
For A, either:
(i) A represents a single bond; optionally substituted C1 to C8 alkylene; a C2 to C12 group having at least one alkene double bond; a 3- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S or xe2x80x94Rxe2x80x94Arxe2x80x94Rxe2x80x2xe2x80x94, where R and Rxe2x80x2 are independently selected from a bond, optionally substituted C1 to C8 alkylene and a C2 to C12 group having at least one alkene double bond; and Ar represents optionally substituted aryl; or
(ii) the structure Nxe2x80x94A(xe2x80x94R4) represents a 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S, Nxe2x80x94A(xe2x80x94R4) being optionally substituted;
B represents a bond or optionally substituted C1 to C5 alkylene;
C represents a mono- or bi-cyclic aromatic ring structure optionally having at least one substituent selected from CN; NR5R6; an optionally substituted C1 to C8 alkyl; optionally substituted C1 to C8 alkoxy; halogen;
D represents hydrogen; optionally substituted C1 to C8 alkyl; or (CH2)bxe2x80x94R, wherein R represents C3 to C8 cycloalkyl;
E is selected from an optionally substituted 3- to 8-membered heterocyclic ring containing is from 1 to 4 heteroatoms independently selected from O, N and S; II; III; IV; V; VI, VII, VIIa, VIIb, VIIc, and VIId, 
wherein het represents an optionally substituted 3- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S;
F is optionally substituted and represents phenyl or a 3- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms independently selected from O, N and S;
For X and V, either:
(iii) X represents N and Y represents CN or H; or X represents CH and Y represents NO2; or
(iv) Xxe2x80x94Y represents O;
For R1 and R2, either:
(v) R1 and R2 are independently selected from hydrogen and optionally substituted C1 to C8 alkyl; or
(vi) R1 and R2 together represent carbonyl; or
(vii) 
xe2x80x83represents an optionally substituted 3- to 8-membered heterocyclic ring containing from 1 to 3 further heteroatoms independently selected from O, N and S, and R2 meets the definition in option (v);
is R3 meets the definition in option (vii) or represents hydrogen or optionally substituted C1 to C8 alkyl;
R4 meets the definition in option (ii) or represents hydrogen or optionally substituted C1 to C8 alkyl;
R5 and R6 are independently selected from H; optionally substituted C1 to C8 alkyl and optionally substituted aryl;
For R7 and R7a, either:
(viii) R7 and R7a are independently selected from H or optionally substituted C1 to C8 alkyl; or
(ix) 
xe2x80x83represents an optionally substituted 3 to 7-membered cycloalkyl ring;
For R8 and R9, either:
(x) R8 is selected from H; optionally substituted C1 to C8 alkyl; optionally substituted aryl; xe2x80x94Rxe2x80x94Ar, where R represents C1 to C8 alkylene and Ar represents optionally substituted aryl; and optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; and R9 is selected from H; optionally substituted C1 to C8 alkyl and optionally substituted aryl; or
(xi) wherein E represents structure II or III, NR8(-R9) represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 3 further heteroatoms independently selected from O, N and S; or
(xii) wherein E represents structure VI, 
xe2x80x83represents an optionally substituted 3- to 8-membered heterocyclic ring optionally containing from 1 to 4 heteroatoms independently selected from O, N and S;
b represents zero or an integer from 1 to 6.
In one embodiment, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof is provided, with the proviso that a compound wherein X represents CH, Y represents NO2, Nxe2x80x94A(xe2x80x94R4) meets the definition in option (ii) and F represents optionally substituted phenyl is excluded.
The present invention also provides a pharmaceutical formulation comprising such a compound and a pharmaceutically acceptable diluent or carrier.
Furthermore, the present invention provides the following uses of the compound:
(a) Use in the manufacture of a medicament, for antagonising gonadotropin releasing hormone activity.
(b) Use in the manufacture of a medicament for administration to a patient, for reducing the secretion of luteinising hormone by the pituitary gland of the patient.
(c) Use in the manufacture of a medicament for administration to a patient, for therapeutically treating and/or preventing a sex hormone related condition in the patient.
The present invention also relates to a method of antagonising gonadotropin releasing hormone activity in a patient, comprising administering the compound to the patient.
In addition, the invention provides a process of producing the compound.